The present invention relates to novel methods and compositions employing β-adrenergic inverse agonists for smoking cessation, particularly for controlling or preventing the suite of physical and physiological symptoms that is associated with cessation of smoking: including but not limited to craving, tremor, cough, productive cough and hypersecretion of mucus occurring in individuals attempting to quit smoking, either under the management of a general practitioner or specialist. Specifically, the present invention relates to compositions and methods providing for the chronic administration of selective or non-selective β2-adrenergic inverse agonists as treatments to assist smoking cessation.
The health hazards of tobacco smoking have been well documented. Tobacco-related diseases are some of the biggest killers in the world and are cited as one of the major causes of premature death in most industrialized countries. In the United States, it is estimated that some 500,000 deaths per year are attributable to smoking-related diseases. A recent study has estimated that as much as one-third of the male population of China will have significantly shortened lifespans because of smoking. It has been calculated that male and female smokers lose an average of 13.2 and 14.5 years of life, respectively, because of smoking.
Among the diseases and conditions that have been linked to smoking are lung cancer, heart disease, diseases of the circulatory system such as Buerger's Disease, emphysema, chronic obstructive pulmonary disease, and vascular stenosis. Additionally, smoking is now suspected as a risk factor in Alzheimer's disease and many other diseases.
Additionally, even for non-smokers, smoking causes significant health risks because of second-hand smoke. Additionally, cigarette smoking can be a substantial financial burden on regular smokers; the cost of cigarettes has greatly increased in recent years, in part due to increased taxes.
Many current smokers desire to quit. However, quitting smoking is extremely difficult for many smokers. Smokers may attempt to quit either on their own, using over-the-counter products and techniques, or in a program that includes pharmacotherapy as well as education, support, reinforcement and follow-up. Failure rates, even under the auspices of the best programs are high, for a number of reasons. Nicotine, present in tobacco smoke, is extremely addictive. In low concentrations, nicotine acts as a stimulant and is the main factor contributing to the dependence-forming properties of tobacco smoking. According to the American Heart Association, nicotine addiction is one of the hardest addictions to break, and the pharmacological and behavioral characteristics that determine tobacco addiction are similar to those that determine addiction to illegal drugs of abuse such as cocaine, heroin, and amphetamines.
When a smoker attempts to quit, he or she frequently encounters withdrawal symptoms similar to the withdrawal symptoms encountered by users of illegal drugs of abuse such as cocaine or heroin. These withdrawal symptoms include both physiological and psychological symptoms, including but not limited to craving, tremor, anxiety agitation, exhaustion, cough, and chest pain. Currently approved drugs for smoking cessation include nicotine replacement, to reduce the effects of nicotine replacement, and anxiolytics such as varenicline or buproprion to address the psychological symptoms of smoking cessation. However, no currently approved drugs address the physiological and anatomical changes associated with smoking cessation. As detailed below, one of the significant physical symptoms is mucus hypersecretion and coughing, which can be extremely uncomfortable and annoying to a cigarette smoker attempting to quit smoking.
A number of smoking cessation aids are currently available; however, these smoking cessation aids have high failure rates, may have significant side effects, and, in some cases, do not assist in breaking nicotine addiction. For example, nicotine replacement as monotherapy or in combination has a high failure rate.
Mucus secretion from the epithelium is an important function and occurs in the nose and in the airways. Mucus provides important protective functions such as prevention of drying and capture of foreign particles. Normal airway epithelium function requires mucociliary clearance in which mucus secreted on the surface of the airway epithelium is moved continually up the airways by beating cilia thereby removing any foreign objects. Lack of mucociliary clearance may be caused by a variety of disruptions such as failure of epithelial ciliary beating, lack of ciliated epithelium, minimal to no mucus secretion or hypersecretion of mucus, or a combination of these. Most importantly, the airway epithelium may undergo reversible phenotypical changes to goblet cells that produce and secrete mucus. Hypersecretion of mucus occurs as a consequence of allergies, viral, bacterial or fungal infections, asthma, cystic fibrosis, or COPD. As indicated above, it also occurs in individuals as the result of attempting smoking cessation.
The physical mechanism of coughing serves to expel the mucus from the airway passages (see e.g., “Foundations of Respiratory Care” Pierson and Kacmarek, eds. (1992) Churchill Livingstone Inc. New York, N.Y.; “Harrison's Principles of Internal Medicine”, Fauci et al., eds. (1997) 14th Edition, McGraw Hill, New York, N.Y.).
The mucociliary system consists of ciliated epithelial cells, epithelial goblet cells, and serous and mucous cells located in submucosal glands. The cilia are surrounded by an aqueous layer (periciliary fluid) secreted into the lumen of the airway passage by the active transport of chloride and the passive movement of water across the epithelium. The cilia make contact with the mucus floating on this aqueous layer, and via a unidirectional propelling motion provide for movement of mucus toward the glottis (see Pierson and Kacmarek, supra and Fauci et al., supra). Mucus is produced by the epithelial goblet cells and submucosal gland cells and is secreted into the lumen of the airway after degranulation.
Mucus is characterized by the presence of a family of glycoproteins known generally as mucins. Mucins are a family of glycoproteins secreted by the epithelial cells including those at the respiratory, gastrointestinal and female reproductive tracts. Mucins are responsible for the viscoelastic properties of mucus and at least eight mucin genes are known. (D. J. Thornton, et al., J. Biol. Chem. 272, 9561-9566 (1997)). Analysis of airway secretions has identified MUC5AC and MUC5B as the primary mucin constituents of the respiratory mucus gel.
While mucus generally facilitates the clearance of inhaled particles or infectious agents, hypersecretion of mucus in the airways may cause progressive airway obstruction. In peripheral airways, cough is ineffective for clearing secretions. Furthermore, because of their small dimensions, small airways containing many goblet cells are especially vulnerable to airway plugging by mucus. Airway hypersecretion affects a substantial number of individuals; it is seen in a variety of pulmonary diseases, such as chronic bronchitis, acute asthma, cystic fibrosis, and bronchiectasis. Also, other conditions such as pulmonary fibrosis and tuberculosis are also characterized by mucus hypersecretion. As indicated above, mucous hypersecretion is a significant symptom in cigarette smokers and smokers attempting smoking cessation, and is frequently responsible for failure of the attempt to cease smoking. Cigarette smoking causes the majority of cases of lung cancer and chronic obstructive pulmonary disease, which consists of chronic bronchitis and emphysema. The definition of chronic bronchitis (reference ATS) reflects mucus hypersecretion for at least 2 months for consecutive years.
Hypersecretion has also been implicated in cystic fibrosis, which is one of the most common fatal genetic diseases in the world. Cystic fibrosis is an autosomal recessive disease that causes the airway mucosal cell to become unresponsive to cyclic-AMP-dependent protein kinase activation of the membrane chloride ion channels (Pierson and Kacmarek, supra and Fauci, et al., supra). The subsequent electrolyte imbalance reduces the level of hydration of the airway mucus, thus resulting in highly viscous mucus in the lungs of an individual afflicted with cystic fibrosis. Hypersecretion obstructs the air passages of individuals with cystic fibrosis, further compromising lung function.
Classical modalities of treating individuals afflicted with chronmic cough and mucus hypersecretion include antibiotic therapy, bronchodilators, use of systemic or inhaled corticosteroids, liquefaction of the mucus by oral administration of expectorants, e.g. guaifenesin (sold under a variety of trade names such as Organidin® or Iophen™) or iodinated glycerol (also sold under a variety of trade names such as Par Glycerol™ or R-Gen™, and aerosol delivery of “mucolytic” agents, such as water or hypertonic saline solution. Cough suppressants include narcotic products such as codeine. Therapy for cystic fibrosis is the administration of DNAse to target the DNA-rich mucus or sputum (Shak, et al (1990) Proc. Nat. Acad. (USA) 87:9188-9192; Hubbard, R. C. et al. (1991) N. Engl. J. Med. 326:812). Other drugs that are used are acetylcysteine (sold under the trade name of Mucomyst™, Mucosil-10™, Mucosil-20™ and others). In addition, chest physical therapy consisting of percussion, vibration and drainage are also used to facilitate clearance of viscous mucus. Specifically, there is a need for a specific modality that will reduce the formation of mucus secretions in the airways, by enabling or causing the reversal of mucus (goblet) cells to ciliated epithelium.
Additionally, antihistamines and decongestants are sometimes used in an attempt to achieve symptomatic relief from respiratory conditions characterized by the presence of excess mucus secretion. Antihistamines, which dry the respiratory tract, have little or no value in treating a cough, except when it is caused by an upper respiratory allergy. With coughs from other causes, such as bronchitis, the drying actions of antihistamines can be harmful, thickening respiratory secretions and making them more difficult to remove.
Currently a number of pharmaceutical substances are indicated for or have been shown to be useful in treating the symptoms of COPD, including salmeterol xinafoate, fluticasone propionate, ipratropium bromide, (2R,3R,4S,5R)-2-[6 amino-2-(1S-hydroxymethyl-2-phenyl-ethylamino)-purin-9-yl]-5-(2-ethyl-2H-tetrazol-5-yl)-tetrahydrofuran-3,4-diol tiotropiurn, 4-hydroxy-7-[2-[[2-[[3-(2-phenylethyoxy)propyl]sulfonyl]ethyl]amino]ethyl-2-(3H)-benzothiazolone and cis-20,4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexanecarboxylic acid. However, there remains a need for the development of specific agents that can reverse mucus hypersecretion and can prevent the transformation of epithelial cells of the respiratory system into goblet cells or reverse goblet cell phenotype to ciliated columnar epithelium. There is a particular need for such agents that can block mucus hypersecretion in individuals experiencing mucus hypersecretion as the result of chronic cough.
More efficient and long-lasting therapeutic modalities that can reverse the anatomical, histological, and physiological changes leading to symptoms that are a consequence of smoking cessation such as tremor, craving, mucus hypersecretion and chronic unproductive or productive cough can bring about the recovery of normal mucociliary clearance in diseased nasal and/or pulmonary airways are needed. Most particularly, there is a need for efficient therapeutic modalities that can treat or block one or more of the suite of symptoms in patients attempting smoking cessation in order to reduce the physical symptoms associated with nicotine withdrawal and increase the effectiveness of smoking cessation programs.